Gene Expression Studies in Down Syndrome: What Do They Tell Us about Disease Phenotypes?

Down syndrome is a well-studied aneuploidy condition in humans, which is associated with various disease phenotypes including cardiovascular, neurological, haematological and immunological disease processes. This review paper aims to discuss the research conducted on gene expression studies during fetal development. A descriptive review was conducted, encompassing all papers published on the PubMed database between September 1960 and September 2022. We found that in amniotic fluid, certain genes such as COL6A1 and DSCR1 were found to be affected, resulting in phenotypical craniofacial changes. Additionally, other genes such as GSTT1, CLIC6, ITGB2, C21orf67, C21orf86 and RUNX1 were also identified to be affected in the amniotic fluid. In the placenta, dysregulation of genes like MEST, SNF1LK and LOX was observed, which in turn affected nervous system development. In the brain, dysregulation of genes DYRK1A, DNMT3L, DNMT3B, TBX1, olig2 and AQP4 has been shown to contribute to intellectual disability. In the cardiac tissues, dysregulated expression of genes GART, ETS2 and ERG was found to cause abnormalities. Furthermore, dysregulation of XIST, RUNX1, SON, ERG and STAT1 was observed, contributing to myeloproliferative disorders. Understanding the differential expression of genes provides insights into the genetic consequences of DS. A better understanding of these processes could potentially pave the way for the development of genetic and pharmacological therapies.

A toolkit for capturing a representative and equitable sample in health research.

Research participants often do not represent the general population. Systematic exclusion of particular groups from research limits the generalizability of research findings and perpetuates health inequalities. Groups considered underserved by research include those whose inclusion is lower than expected based on population estimates, those with a high healthcare burden but limited research participation opportunities and those whose healthcare engagement is less than others. The REP-EQUITY toolkit guides representative and equitable inclusion in research. The toolkit was developed through a methodological systematic review and synthesis and finalized in a consensus workshop with 24 participants. The REP-EQUITY toolkit describes seven steps for investigators to consider in facilitating representative and equitable sample selection. This includes clearly defining (1) the relevant underserved groups, (2) the aims relating to equity and representativeness, (3) the sample proportion of individuals with characteristics associated with being underserved by research, (4) the recruitment goals, (5) the strategies by which external factors will be managed, (6) the methods by which representation in the final sample will be evaluated and (7) the legacy of having used the toolkit. Using the REP-EQUITY toolkit could promote trust between communities and research institutions, increase diverse participation in research and improve the generalizability of health research. National Institute for Health and Care Research PROSPERO identifier: CRD42022355391.

Sensitivity of Two-Tiered Lyme Disease Serology in Children With an Erythema Migrans Lesion.

In our prospective cohort of 192 children with a physician-diagnosed erythema migrans (EM) lesion, two-tier Lyme disease serology had higher sensitivity in children with multiple EM lesions (76.8% multiple lesions vs. 38.1% single EM; difference 38.7%, 95% confidence interval 24.8%-50.4%). The diagnosis of cutaneous Lyme disease should be based on careful physical examination rather than laboratory testing.

"I think it is woven through me, and sadly that means it is woven through our family life": the experiences and support needs of mothers with eating disorders.

BACKGROUND: Eating disorders may disrupt parenting, and there is evidence to suggest that the children of parents with eating disorders are at greater risk for the development of eating disorders themselves. This study sought to broaden and extend current understandings of the lived experiences of mothers who have eating disorders. METHOD: A qualitative study using thematic analysis was conducted. Eighteen mothers living in the UK, USA, and Australia took part in semi-structured online interviews. Participants were mothers to at least one child aged two years or older, had received a lifetime diagnosis of one or more eating disorders, and reported experiencing symptoms since becoming a parent. RESULTS: Data were analysed using an inductive approach to reflexive thematic analysis. Four major themes, each with subthemes, were identified. These were: parenthood as a double-edged sword; the eating disorder impacts on parenting; blame and burden; and seeking support. CONCLUSIONS: The lived experiences of mothers indicate a complex relationship between eating disorders and parenthood. While parenting can impact eating disorders, eating disorders can also impact parenting, in a range of ways that extend beyond the domains of food, eating and the body. There is a pressing need for the development of specialised, non-judgemental support options for parents with eating disorders and their families.

Many adults with eating disorders are parents. Previous research studies suggest that these parents may experience particular challenges in relation to parenting, and that their children may be at greater risk of developing eating disorders themselves. We interviewed eighteen mothers who had at some point in their life been diagnosed with an eating disorder, and had experienced symptoms since becoming a parent. Interview data were analysed and four themes were identified to describe the lived experiences of mothers who have eating disorders. These themes, which we refer to as 'parenthood as a double-edged sword', 'the eating disorder impacts on parenting', 'blame and burden', and 'seeking support' suggest a complex relationship between eating disorders and being a parent. Parenting can impact eating disorders, and eating disorders can also impact parenting. The mothers who participated in our study also identified unique challenges when seeking treatment, and there is a need for support options to be developed specifically for parents with eating disorders, and for their families.

Biomarkers for Pediatric Bacterial Musculoskeletal Infections in Lyme Disease-Endemic Regions.

OBJECTIVES: Bacterial musculoskeletal infections (MSKIs) are challenging to diagnose because of the clinical overlap with other conditions, including Lyme arthritis. We evaluated the performance of blood biomarkers for the diagnosis of MSKIs in Lyme disease-endemic regions. METHODS: We conducted a secondary analysis of a prospective cohort study of children 1 to 21 years old with monoarthritis presenting to 1 of 8 Pedi Lyme Net emergency departments for evaluation of potential Lyme disease. Our primary outcome was an MSKI, which was defined as septic arthritis, osteomyelitis or pyomyositis. We compared the diagnostic accuracy of routinely available biomarkers (absolute neutrophil count, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin) to white blood cells for the identification of an MSKI using the area under the receiver operating characteristic curve (AUC). RESULTS: We identified 1423 children with monoarthritis, of which 82 (5.8%) had an MSKI, 405 (28.5%) Lyme arthritis, and 936 (65.8%) other inflammatory arthritis. When compared with white blood cell count (AUC, 0.63; 95% confidence interval [CI], 0.55-0.71), C-reactive protein (0.84; 95% CI, 0.80-0.89; P < .05), procalcitonin (0.82; 95% CI, 0.77-0.88; P < .05), and erythrocyte sedimentation rate (0.77; 95% CI, 0.71-0.82; P < .05) had higher AUCs, whereas absolute neutrophil count (0.67; 95% CI, 0.61-0.74; P < .11) had a similar AUC. CONCLUSIONS: Commonly available biomarkers can assist in the initial approach to a potential MSKI in a child. However, no single biomarker has high enough accuracy to be used in isolation, especially in Lyme disease-endemic areas.

Multiplex High-Definition Polymerase Chain Reaction Assay for the Diagnosis of Tick-borne Infections in Children.

Background: Ixodes scapularis ticks can carry Borrelia species as well as other pathogens that cause human disease. The frequency of tick-borne infections and coinfections in children with suspected Lyme disease is unknown, creating clinical uncertainty about the optimal approach to diagnosis. Methods: We enrolled children aged 1-21 years presenting to 1 of 8 Pedi Lyme Net emergency departments for evaluation of Lyme disease. We selected cases with serologically or clinically diagnosed Lyme disease (erythema migrans or early neurologic disease) matched by symptoms, age, gender, and center to control subjects without Lyme disease. We tested whole blood samples collected at the time of diagnosis using a multiplex high-definition polymerase chain reaction (HDPCR) panel to identify 9 bacterial or protozoan pathogens associated with human disease. We compared the frequency of tick-borne coinfections in children with Lyme disease to matched controls. Results: Of the 612 selected samples, 594 (97.1%) had an interpretable multiplex HDPCR result. We identified the following non-Borrelia tick-borne infections: Anaplasma phagocytophilum (2), Ehrlichia chaffeensis (1), and Babesia microti (12). Children with Lyme disease were more likely to have another tick-borne pathogen identified than matched controls (15/297 [5.1%] Lyme cases vs 0/297 [0%]; difference, 5.1% [95% confidence interval, 2.7%-8.2%]). Conclusions: Although a substantial minority of children with Lyme disease had another tick-borne pathogen identified, either first-line Lyme disease antibiotics provided adequate treatment or the coinfection was subclinical and did not require specific treatment. Further studies are needed to establish the optimal approach to testing for tick-borne coinfections in children.

Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology. We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies. Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic-environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.

Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: A multicenter pediatric emergency medicine perspective.

Children with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE) due to sickling of erythrocytes, which often requires care in the emergency department. Our objective was to assess the use and impact of intranasal fentanyl for the treatment of children with SCD-VOE on discharge from the emergency department in a multicenter study. We conducted a cross-sectional study at 20 academic pediatric emergency departments in the United States and Canada. We used logistic regression to test bivariable and multivariable associations between the outcome of discharge from the emergency department and candidate variables theoretically associated with discharge. The study included 400 patients; 215 (54%) were female. The median age was 14.6 (interquartile range 9.8, 17.6) years. Nineteen percent (n = 75) received intranasal fentanyl in the emergency department. Children who received intranasal fentanyl had nearly nine-fold greater adjusted odds of discharge from the emergency department compared to those who did not (adjusted odds ratio 8.99, 95% CI 2.81-30.56, p < .001). The rapid onset of action and ease of delivery without intravenous access offered by intranasal fentanyl make it a feasible initial parenteral analgesic in the treatment of children with SCD presenting with VOE in the acute-care setting. Further study is needed to determine potential causality of the association between intranasal fentanyl and discharge from the emergency department observed in this multicenter study.

Racial Differences in the Diagnosis of Lyme Disease in Children.

Black children with Lyme disease compared with children of other races were less likely to have an erythema migrans lesion diagnosed (adjusted odds ratio, 0.34; 95% confidence interval, .14-.79) but more likely to have a swollen joint (adjusted odds ratio, 3.68; 95% confidence interval, 2.13-6.36) after adjustment for age and local Lyme incidence.

Rethinking Blood Testing in Pediatric Cancer Patients: A Quality Improvement Approach.

Introduction: The overuse of blood tests burdens the healthcare system and can detrimentally impact patient care. Risks of frequent blood sampling include infection and clinician-induced anemia, which can negatively impact patients and their families. Pediatric cancer patients are particularly vulnerable as they are immunocompromised with a small blood volume. Four blood tests had become a daily practice. Therefore, we aimed to reduce the number of blood tests taken per bed day within the inpatient pediatric cancer unit by 15% within 8 months. Methods: This quality improvement project combined several strategies to reduce test frequency and empower clinicians on the rationale for blood test ordering. Recommendations were developed collaboratively presented in a summary table. Targeted behavior-change methodology built engagement and momentum for the change. All clinicians were challenged to STOP and THINK about why a test is necessary for each patient. The primary outcome measure was the frequency of the tests taken per bed day. Frequency was compared between pre- and postimplementation plus follow-up periods across 2019-2021. Results: 26,941 blood tests were captured in 1,558 admissions. The intervention led to an overall blood test reduction of 37% over 8 months. Liver Function Tests were the standout, with a 52% decrease in test frequency. Conclusions: A strategy incorporating education and culture change, combined with clear guidance on testing frequency, significantly reduced the ordering frequency of blood tests without increased patient harm.

The impact of treating parental anxiety on children's mental health: An empty systematic review.

Children of anxious parents are at heightened risk of developing an anxiety disorder of their own, but promising research indicates that targeting parenting behaviours can reduce the risk of intergenerational transmission of anxiety. Given there is extensive evidence for the efficacy of treatments for adult anxiety, the current review sought to identify whether interventions solely addressing parental symptoms had any effect on the mental health and wellbeing of their children. Randomised Controlled Trials of psychological interventions targeting adults with a probable anxiety disorder and which included a child mental health or wellbeing outcome were eligible for inclusion. Scopus, Web of Science, PubMed, PsychINFO, and PsychArticles were searched, and 2137 articles were systematically reviewed. However, no articles were identified that met the review criteria. Research into interventions targeting adult anxiety is failing to consider the potential benefit treatment may have on dependent children. This is a missed opportunity to evaluate a potential means of support for children who are known to be at risk of anxiety. Evaluation of psychological interventions for adult anxiety should consider including both adult and child mental health outcomes to determine potential preventative effects.

Identification of Digital Health Priorities for Palliative Care Research: Modified Delphi Study.

BACKGROUND: Developments in digital health have the potential to transform the delivery of health and social care to help citizens manage their health. Currently, there is a lack of consensus about digital health research priorities in palliative care and a lack of theories about how these technologies might improve care outcomes. Therefore, it is important for health care leaders to identify innovations to ensure that an increasingly frail population has appropriate access to palliative care services. Consequently, it is important to articulate research priorities as the first step in determining how finite resources should be allocated to a field saturated with rapidly developing innovation. OBJECTIVE: The aim of this study is to identify research priority areas for digital health in palliative care. METHODS: We selected digital health trends, most relevant to palliative care, from a list of emerging trends reported by a leading institute of quantitative futurists. We conducted 2 rounds of the Delphi questionnaire, followed by a consensus meeting and public engagement workshop to establish a final consensus on research priorities for digital technology in palliative care. We used the views of public representatives to gain their perspectives on the agreed priorities. RESULTS: A total of 103 experts (representing 11 countries) participated in the first Delphi round. Of the 103 experts, 55 (53.3%) participated in the second round. The final consensus meetings were attended by 10.7% (11/103) of the experts. We identified 16 priority areas, which involved many applications of technologies, including care for patients and caregivers, self-management and reporting of diseases, education and training, communication, care coordination, and research methodology. We summarized the priority areas into eight topics: big data, mobile devices, telehealth and telemedicine, virtual reality, artificial intelligence, smart home, biotechnology, and digital legacy. CONCLUSIONS: The priorities identified in this study represent a wide range of important emerging areas in the fields of digital health, personalized medicine, and data science. Human-centered design and robust governance systems should be considered in future research. It is important that the risks of using these technologies in palliative care are properly addressed to ensure that these tools are used meaningfully, wisely, and safely and do not cause unintentional harm.

A Systematic Review and Lived-Experience Panel Analysis of Hopefulness in Youth Depression Treatment.

Hopefulness is arguably of central importance to the recovery of youth with major or complex youth depression, yet it is unclear how hopefulness can best be enhanced in treatment. A narrative synthesis of published and grey literature was combined with new insights from a youth lived-experience panel (N = 15), focusing on to what extent and how specific psychological therapies and standard mental health care scaffold hopefulness as applied to depression among 14-25-year-olds. Thirty-one studies of variable quality were included in this review; thirteen were qualitative, thirteen quantitative, and five used mixed methods. Hopefulness is an important active ingredient of psychotherapies and standard mental health care in youth depression. Evidence suggests talking and activity therapies have moderate to large effects on hopefulness and that hopefulness can be enhanced in standard mental health care. However, varying intervention effects suggest a marked degree of uncertainty. Hopefulness is best scaffolded by a positive relational environment in which there is support for identifying and pursuing personally valued goals and engaging in meaningful activity. Animated (https://www.youtube.com/watch?v=o4690PdTGec) and graphical summaries (https://doi.org/10.13140/RG.2.2.27024.84487) are available. Supplementary Information: The online version contains supplementary material available at 10.1007/s40894-021-00167-0.

Medium-term mortality after hip fractures and COVID-19: A prospective multi-centre UK study.

PURPOSE: The COVID-19 pandemic has caused 1.4 million deaths globally and is associated with a 3-4 times increase in 30-day mortality after a fragility hip fracture with concurrent COVID-19 infection. Typically, death from COVID-19 infection occurs between 15 and 22 days after the onset of symptoms, but this period can extend up to 8 weeks. This study aimed to assess the impact of concurrent COVID-19 infection on 120-day mortality after a fragility hip fracture. METHODS: A multi-centre prospective study across 10 hospitals treating 8% of the annual burden of hip fractures in England between 1st March and 30th April, 2020 was performed. Patients whose surgical treatment was payable through the National Health Service Best Practice Tariff mechanism for "fragility hip fractures" were included in the study. Patients' 120-day mortality was assessed relative to their peri-operative COVID-19 status. Statistical analysis was performed using SPSS version 27. RESULTS: A total of 746 patients were included in this study, of which 87 (11.7%) were COVID-19 positive. Mortality rates at 30- and 120-day were significantly higher for COVID-19 positive patients relative to COVID-19 negative patients (p < 0.001). However, mortality rates between 31 and 120-day were not significantly different (p = 0.107), 16.1% and 9.4% respectively for COVID-19 positive and negative patients, odds ratio 1.855 (95% CI 0.865-3.978). CONCLUSION: Hip fracture patients with concurrent COVID-19 infection, provided that they are alive at day-31 after injury, have no significant difference in 120-day mortality. Despite the growing awareness and concern of "long-COVID" and its widespread prevalence, this does not appear to increase medium-term mortality rates after a hip fracture.

The Unfolding of Cognitive Effort During Sentence Processing: Pupillometric Evidence From People With and Without Aphasia.

PURPOSE: Arousal and cognitive effort are relevant yet often overlooked components of attention during language processing. Pupillometry can be used to provide a psychophysiological index of arousal and cognitive effort. Given that much is unknown regarding the relationship between cognition and language deficits seen in people with aphasia (PWA), pupillometry may be uniquely suited to explore those relationships. The purpose of this study was to examine arousal and the time course of the allocation of cognitive effort related to sentence processing in people with and without aphasia. METHOD: Nineteen PWA and age- and education-matched control participants listened to relatively easy (subject-relative) and relatively difficult (object-relative) sentences and were required to answer occasional comprehension questions. Tonic and phasic pupillary responses were used to index arousal and the unfolding of cognitive effort, respectively, while sentences were processed. Group differences in tonic and phasic responses were examined. RESULTS: Group differences were observed for both tonic and phasic responses. PWA exhibited greater overall arousal throughout the task compared with controls, as evidenced by larger tonic pupil responses. Controls exhibited more effort (greater phasic responses) for difficult compared with easy sentences; PWA did not. Group differences in phasic responses were apparent during end-of-sentence and postsentence time windows. CONCLUSIONS: Results indicate that the attentional state of PWA in this study was not consistently supportive of adequate task engagement. PWA in our sample may have relatively limited attentional capacity or may have challenges with allocating existing capacity in ways that support adequate task engagement and performance. This work adds to the body of evidence supporting the validity of pupillometric tasks for the study of aphasia and contributes to a better understanding of the nature of language deficits in aphasia. Supplemental Material https://doi.org/10.23641/asha.16959376.

Parental eating disorders: A systematic review of parenting attitudes, behaviours, and parent-child interactions.

A substantial proportion of adults with eating disorders are parents. Studies suggest these parents may experience a range of parenting challenges, and their children may be at an increased risk for the development of eating disorders themselves. With parenting practices being one potential environmental mechanism for the intergenerational transmission of eating disorders, we systematically searched Scopus, Web of Science, PubMed, MEDLINE, PsychINFO, and PsychArticles for controlled studies in which parenting attitudes, behaviours, and parent-child interactions were examined for parents with and without probable eating disorders. 26,512 abstracts were screened, and 167 full-text manuscripts were retrieved, with 33 studies meeting the review inclusion criteria. Studies suggest that parents with eating disorders experience higher levels of parenting stress than control parents, and may on average be more intrusive, less sensitive, and provide less structuring/facilitation in non-feeding interactions with their children. These parents also appear, on average, to experience increased concern about their children's weight, and parent-child mealtime interactions may be problematic and characterised by high levels of conflict. Suggestions for future research are made with a view to enhancing understandings of the intergenerational transmission of eating disorders, which may lead to the identification of intervention targets for parents with eating disorders and their children.

How do hospitals help patients prepare for and participate in outpatient clinics?

BACKGROUND: Patients attending general medicine outpatient clinics (GM OPC) at hospital face multiple healthcare demands in an environment that has evolved with the clinician at its centre. The ideas, knowledge and understanding that patients bring to their clinic appointments are not well studied in the New Zealand setting. AIMS: To assess how hospitals prepare patients for their outpatient appointments and encourage people to participate actively in their own care. METHODS: A prospective survey of 50 patients attending follow-up GM OPC was performed. Participants' understanding of the purpose of their appointment and knowledge of their prescription medications was explored using a nine-item questionnaire. Patient-directed hospital communication was then analysed to assess the information supplied to patients. RESULTS: Two-thirds (66%) of participants attending follow-up GM OPC recalled being informed of an appointment at the time of leaving hospital; only half (54%) felt they had been informed of the purpose of these appointments. Patient-directed communication was not completed in half (50%) of the analysed discharge letters. One-third (36%) of participants did not have specific questions for their clinic visits. CONCLUSIONS: Limited information and support is provided to patients attending follow-up GM OPC and is not tailored to individuals' health literacy. This practice assumes patients have comparable health literacy to clinicians, which may have downstream impacts on the usefulness of the clinic experience. The information that health users bring to clinic may be improved by increasing pre-clinic user engagement and deploying patient-centred tools within the healthcare environment.